Abstract Anterior cruciate ligament (ACL) reconstruction surgery results in protracted quadriceps weakness that is associated with poorer outcomes, altered biomechanics and heightened risk of subsequent injuries. Little progress has been made in improving quadriceps strength and functional outcomes in the past decade. Alterations in the cellular and morphological composition of the knee extensor muscles contribute to weakness following an ACL reconstruction. ACL reconstruction induces expression of myostatin, a negative regulator of muscle growth, locally within the quadriceps. In addition to mitigating muscle regrowth, myostatin also promotes connective tissue synthesis through activation of figrogenic cells within muscle. The objective of this proposal is to determine the time course of deleterious changes to the injured ligament and limb muscle and identify myostatin as integral in the etiology of protracted muscle weakness in individuals following an ACL tear. Aim 1 will evaluate the timeframe of myostatin induction within the injured ACL and quadriceps. Aim 2 will determine the deleterious changes within the muscle using a mouse model of ACL injury and the efficacy of follistatin and a soluble form of the myostatin receptor (activin 2B receptor) to mitigate these maladaptations. Experiments in aim 3 will determine if the competitive inhibition of myostatin is capable of rescuing ACL injury- induced skeletal muscle weakness. Finally, aim 4 will define if the acute induction of myostatin signaling following an ACL injury in human subjects predicts reductions in muscle strength, connective tissue infiltration and dysregulation of skeletal muscle progenitor cells. The identification of myostatin as a therapeutic target will establish the basis for further research to mitigate myostatin signaling after ACL and other ligamentous injuries to improve rehabilitative efforts and patient recovery.